title: Rapid donor T-cell engraftment increases the risk of chronic graft-versus-host disease following salvage allogeneic peripheral blood hematopoietic cell transplantation for bone marrow failure syndromes.
abstract: The risk of graft-rejection after allogeneic hematopoietic cell transplantation using conventional cyclophosphamide-based conditioning is increased in patients with bone marrow failure syndromes (BMFS) who are heavily transfused and often HLA-alloimmunized. Fifty-six patients with BMFS underwent fludarabine-based reduced-intensity conditioning and allogeneic peripheral blood progenitor cell (PBPC) transplantation at a single institution. The conditioning regimen consisted of intravenous cyclophosphamide, fludarabine, and equine antithymocyte globulin. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine A alone or in combination with either mycophenolate mofetil or methotrexate. To reduce the risk of graft-rejection/failure, unmanipulated G-CSF mobilized PBPCs obtained from an HLA-identical or single HLA-antigen mismatched relative were transplanted rather than donor bone marrow. Despite a high prevalence of pretransplant HLA-alloimmunization (41%) and a heavy prior transfusion burden, graft-failure did not occur with all patients having sustained donor lympho-hematopoietic engraftment. The cumulative incidence of grade II-IV acute-GVHD and chronic-GVHD was 51.8% and 72%, respectively; with 87.1% surviving at a median follow-up of 4.5 years. A multivariate analysis showed pretransplant alloimmunization and rapid donor T-cell engraftment (≥95% donor by day 30) were both significantly (P < 0.05) associated with the development of chronic-GVHD (adjusted HR 2.13 and 2.99, respectively). These data show fludarabine-based PBPC transplantation overcomes the risk of graft-failure in patients with BMFS, although rapid donor T-cell engraftment associated with this approach appears to increase the risk of chronic-GVHD. (Clinicaltrials.gov identifier: NCT00003838).
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland; Division of Hematology, Medical Oncology and BMT, Department of Medicine, Georgia Regents University, Georgia.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Pantin
authors.forename: Xin
authors.initials: X
authors.lastname: Tian
authors.forename: Avni A
authors.initials: AA
authors.lastname: Shah
authors.forename: Roger
authors.initials: R
authors.lastname: Kurlander
authors.forename: Catalina
authors.initials: C
authors.lastname: Ramos
authors.forename: Lisa
authors.initials: L
authors.lastname: Cook
authors.forename: Hahn
authors.initials: H
authors.lastname: Khuu
authors.forename: David
authors.initials: D
authors.lastname: Stroncek
authors.forename: Susan
authors.initials: S
authors.lastname: Leitman
authors.forename: John
authors.initials: J
authors.lastname: Barrett
authors.forename: Theresa
authors.initials: T
authors.lastname: Donohue
authors.forename: Neal S
authors.initials: NS
authors.lastname: Young
authors.forename: Nancy
authors.initials: N
authors.lastname: Geller
authors.forename: Richard W
authors.initials: RW
authors.lastname: Childs
mesh_terms: D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic; D000961:Antilymphocyte Serum / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D002648:Child; D002908:Chronic Disease; D016572:Cyclosporine / Q000008:administration & dosage; D005260:Female; D006084:Graft Rejection / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D006086:Graft vs Host Disease / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006457:Hemoglobinuria, Paroxysmal / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D036102:Peripheral Blood Stem Cell Transplantation; D012307:Risk Factors; D016879:Salvage Therapy; D013601:T-Lymphocytes; D013997:Time Factors; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D055815:Young Adult
chemical_list: D000961:Antilymphocyte Serum; D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D016179:Granulocyte Colony-Stimulating Factor; D016572:Cyclosporine; D014740:Vidarabine; D009173:Mycophenolic Acid; C024352:fludarabine